Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes
Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranesVictoria Campuzano, Laura Montermini1, Yves Lutz, Lidia Cova1,2, Colette Hindelang, Sarn Jiralerspong1, Yvon Trottier, Stephen J. Kish3, Baptiste Faucheux4, Paul Trouillas5, François J. Authier6, Alexandra Dürr4, Jean-Louis Mandel, Angelo Vescovi2, Massimo Pandolfo1,7,8 and Michel Koenig*
Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM-CNRS-ULP, Illkirch, France, 1Centre de Recherche du CHUM, Pavillon Notre Dame, Montréal, Canada, 2Laboratory of Neuropharmacology, Istituto Nazionale Neurologico `C.Besta', Milan, Italy, 3Clarke Institute of Psychiatry, Toronto, Canada, 4Hôpital Pitié-Salpêtrière, Paris, France, 5Hôpital Neurologique et Neuro-Chirurgical Pierre Wertheimer, Lyon, France, 6Hôpital Henri Mondor, Creteil, France, 7Département de Médecine, Université de Montréal, Montréal, Canada and 8Department of Neurology and Neurosurgery, McGill University, Montréal, Canada
Received April 29, 1997;Revised and Accepted July 23, 1997
Friedreich ataxia is a progressive neurodegenerative disorder caused by loss of function mutations in the frataxin gene. In order to unravel frataxin function we developed monoclonal antibodies raised against different regions of the protein. These antibodies detect a processed 18 kDa protein in various human and mouse tissues and cell lines that is severely reduced in Friedreich ataxia patients. By immunocytofluorescence and immunocytoelectron microscopy we show that frataxin is located in mitochondria, associated with the mitochondrial membranes and crests. Analysis of cellular localization of various truncated forms of frataxin expressed in cultured cells and evidence of removal of an N-terminal epitope during protein maturation demonstrated that the mitochondrial targetting sequence is encoded by the first 20 amino acids. Given the shared clinical features between Friedreich ataxia, vitamin E deficiency and some mitochondriopathies, our data suggest that a reduction in frataxin results in oxidative damage.
Progressive neurodegenerative diseases are conditions that unrelentingly lead to severe physical disability or death. Neurons with long myelinated axons running through the spinal cord are affected by many of these diseases. These neurons may be considered giant cells, which must bear a heavy burden for cell maintenance and the underlying energy needs. The largest neurons in the human body are those located in the dorsal root ganglia of the spinal cord. The corresponding axons, that may be more than 1 m long, run from the peripheral sensory endings through the sensory nerves and the posterior columns of the spinal cord, up to the medulla oblongata. These neurons are primarily affected in Friedreich ataxia (FRDA), an autosomal recessive progressive neurodegenerative disorder which is the most common cause of inherited ataxia in the Caucasian population (1 ). Other sites of neurodegeneration in Friedreich ataxia involve neurons of the spinocerebellar and corticospinal tracts (2 ). Non-neuronal lesions are also found in Friedreich ataxia, including hypertrophic cardiomyopathy present in most patients. Diabetes or glucose intolerance are common and possibly relate to pancreatic deficiency. All the involved tissues are highly sensitive to impaired energy production, as evidenced by their frequent involvement in mitochondrial diseases (3 ).
Friedreich ataxia is most commonly caused by a large GAA triplet repeat expansion within the first intron of the gene encoding frataxin (4 ). The majority of patients (~95%) are homozygous for the GAA repeat expansion and the remaining 5% are compound heterozygous for the expansion and a point mutation affecting the frataxin coding sequence. In patients homozygous for the expansion there is a correlation between the number of GAA repeats on the smaller allele and age of onset, disease progression and cardiomyopathy (5 -9 ), confirming that the expansion is the primary cause of the disease. The expansion causes severely reduced levels of mature frataxin mRNA (4 ,10 ). The existence of nonsense and splice mutations leading to the same clinical presentation as homozygous expansions and the reduced levels of frataxin mRNA found associated with homozygous expansions indicate that Friedreich ataxia is due to loss of frataxin function.
Frataxin is a predicted 210 amino acid protein with no homology with proteins of known function. Related genes have been found in the mouse (11 ) and, as anonymous open reading frames (ORFs), in the nematode Caenorhabditis elegans and in yeast (4 ). Frataxin also shows low but significant similarity with the CyaY proteins of Gram-negative bacteria, whose function is unknown (12 ). The domain encoded by human exons 3-5 shows the highest conservation throughout evolution.
In order to unravel how frataxin loss of function causes the disease, we sought to identify frataxin in cells of normal and affected individuals. We developed specific monoclonal antibodies (mAbs) raised against different regions of the protein. These mAbs detect an 18 kDa protein that is severely reduced in tissues of FRDA patients. An inverse correlation was observed between the amount of protein and expansion size on the smaller allele. Using immunofluorescence and immunoelectron microscopy we show that frataxin localizes within the mitochondria and we found that the mitochondrial target sequence is encoded by exon 1 of the frataxin gene.
In order to develop mAbs against frataxin the complete coding sequence of human frataxin was cloned in the prokaryotic expression vector pATH (13 ). Overexpression of pATH constructs in Escherichia coli produced fusion proteins (containing the TrpE bacterial protein at the N-terminal end) as inclusion bodies, which were isolated and injected into mice to generate antibodies. Peptide A, a potentially immunogenic peptide from the N-terminus (Fig. 1 A), was also injected into mice for mAb production. Mice sera and supernatants of positive hybridoma clones were tested by Western blot of transfected COS-1 cells overexpressing the full-length frataxin protein. Five specific hybridomas were established, 1D4, 2D4, 2F10 and 1G2 raised against the fusion protein and 1H1 raised against N-terminal peptide A. Under our experimental conditions endogenous frataxin was undetectable in non-transfected COS-1 cells. On Western blots of transfected COS-1 cells all mAbs detected an ~30 kDa protein and smaller products that showed intensity pattern variations, depending on the antibody used (Fig. 1 B). The full-length 30 kDa frataxin expressed in COS-1 cells was identical in size to the in vitro translated protein (data not shown), excluding the possibility of major post-translational modification.
Our strongest reacting antibody, mAb 1G2, was used to detect endogenous frataxin on Western blots of normal human muscle, heart, cerebellum and spinal cord extracts. In all tissues the 1G2 antibody detected an 18 kDa protein corresponding to one of the major smaller products observed in transfected COS-1 cells (Fig. 2 ). This indicates that frataxin is processed into a smaller mature form by proteolytic cleavage, the larger products presumably representing intermediates of the maturation process. The same, though fainter, band was obtained with mAbs 1D4 (Fig. 2 A) and 2F10. mAbs 1H1 and 2D4 failed to detect endogenous frataxin, indicating that the N-terminal epitope they recognize is removed during maturation.
A major clue for unravelling the function of a new protein is to identify its subcellular localization. Immunocytofluorescence with antibody 1G2 revealed granular cytoplasmic staining in transfected COS-1 and HeLa cells overexpressing frataxin (Fig. 3 A), as well as in non-transfected cultured mouse astroglial and neuronal cells with only endogenous frataxin expression (Fig. 3 B). Staining often appeared elongated and sometimes fibrillar, a typical morphology for mitochondria. To confirm the mitochondrial identity of the frataxin-positive cytoplasmic organelles, double indirect immunocytofluorescence was first performed in transfected HeLa cells. Identical staining was obtained with both mAb 1G2 (red) and an autoimmune anti-mitochondrial antibody (Menarini Diagnostic; green). Co-localization of the two antibodies was demonstrated by the appearance of an intermediate colour (yellow; Fig. 3 A). Subcellular localization of frataxin was not altered by overexpression, since identical staining was again obtained in non-transfected mouse astroglial and neuronal cells using mAb 1G2 (red) and MitoTracker Green (Molecular Probes), a mitochondrial-specific fluorescent dye (Fig. 3 B). Frataxin staining appeared very strong in the axons of cultured neurons, corresponding to the high number of mitochondria in axons, where high energy consumption takes place.
The discovery of a large intronic trinucleotide expansion as the cause of an autosomal recessive disease was unexpected and raised the question of the pathogenetic mechanisms involved. Initial experiments, first by semi-quantitative PCR (4 ) and then by RNase protection (10 ), indicated that the level of frataxin RNA is severely reduced in patients. These results, and the finding of truncating point mutations in the frataxin gene causing the same clinical presentation (4 ), suggested a loss of function mechanism, in accordance with the recessive mode of inheritance of the disease. In order to unravel the function disrupted by frataxin mutations and to directly test the steady-state amount of frataxin present in patients, we raised specific monoclonal antibodies. The molecular weight of the full-length frataxin molecule produced from an eukaryotic expression vector appeared larger than predicted (30 versus 23 kDa), suggesting either post-translational modification or aberrant electrophoretic mobility. The identity in size with full-length frataxin produced in an in vitro translation assay indicated that frataxin has aberrant electrophoretic mobility. The finding of smaller products in overexpressing COS-1 cells suggested that frataxin is processed. Detection of endogenous frataxin in human tissues confirmed this hypothesis. A single 18 kDa protein is detected with mAbs 1G2, 1D4 and 2F10 and corresponds to the major processed form seen in overexpressing COS-1 cells. The absence of detection of the mature frataxin form with mAbs 1H1 and 2D4 indicates that the N-terminus is removed during processing at least up to the end of exon 1, which accounts for ~6 kDa of the total size decrease.
The severe reduction in the amount of the 18 kDa protein observed in muscle and lymphoblastoid cell lines from FRDA patients proves that it is indeed frataxin and is in full agreement with the previously observed reduction in the frataxin transcript (10 ). Clinical and molecular studies of a large series of patients demonstrated that the length of the smaller expanded allele accounts for 50% of the variance in age of onset, suggesting that a milder presentation might be the consequence of higher residual frataxin present in the tissues of patients (5 -9 ). We found an inverse correlation between the amount of protein produced in lymphoblastoid cell lines of seven typical FRDA patients and the length of the repeat expansion on the smaller allele. Strong departure from the curve was observed in a single, almost asymptomatic `Acadian' patient. Interestingly, FRDA patients of `Acadian' origin have a significantly milder phenotype which could not be accounted for by differences in expansion size or by differences in the frataxin coding sequence (7 ). Reduction of frataxin amount appears therefore to represent the molecular basis of the clinical variability in severity and age of onset and is a consequence of the expansion mutation. The finding in the single `Acadian' patient, if confirmed in additional cases from the same population, suggests, however, the existence of sequence variants resulting in higher expression of the frataxin gene.
A study based on the identification of very rare transcripts suggested that Friedreich ataxia might be due to a defect of hybrid molecules comprising both frataxin and a phosphatidylinositol-4-phosphate 5-kinase domain encoded by the neighbouring gene (16 ). The significance of these rare transcripts in relation to the pathology is highly questionable, particularly in the light of a Friedreich ataxia-causing mutation in the initiating ATG that is not translated in any of the described rare hybrid transcripts (10 ). We show here that in several tissues there is a single small protein containing frataxin sequences. The results fit well with the presence of a major transcript detected on Northern blots (4 ). A hybrid molecule containing both frataxin and the phosphatidylinositol-4-phosphate 5-kinase domain would have a larger molecular weight and therefore cannot be the 18 kDa protein absent in Friedreich ataxia patients, seriously challenging the role of phosphatidylinositol-4-phosphate 5-kinase in the pathology of the disease.
We sought to define the subcellular localization of frataxin, as a first step in unraveling its function. Frataxin clearly appears to be localized in mitochondria in both overexpressing, transfected cells and non-transfected astrocytes and neurons, the latter being a cell type that degenerates in FRDA. This subcellular localization clarifies several aspects of frataxin expression and phylogeny. Frataxin is highly expressed in tissues that are rich in mitochondria, such as liver, heart, pancreas and muscle (4 ), but also in brown fat, thymus and kidney (11 ). Frataxin is highly conserved throughout evolution (4 ) and its most distant relative is the CyaY protein of Gram-negative bacteria. The fact that Gram-negative bacteria share a common ancestor with the precursor of eukaryotic mitochondria led Gibson et al. (12 ) to speculate that the frataxin gene might be an ancestral mitochondrial gene that underwent transfer to the nuclear genome during mitochondrial/host cell endosymbiosis. Knock-out of the yeast frataxin counterpart led to a rho- phenotype with deficiency of mitochondrial respiration (11 ,17 ,18 ). The biochemical defect in patients must certainly be more subtle than in yeast, in order to account for the very slowly progressive nature of the disease, possibly reflecting the presence of residual frataxin. No alteration in mitochondrial DNA of Friedreich ataxia patients has been observed in 10 lymphoblastoid cell lines and two heart samples tested by large fragment PCR (19 ; A.Rötig, personal communication) and in one heart and three brain samples tested by Southern blot (M.Pandolfo and E.Shoubridge, unpublished results). The mitochondrial localization of frataxin definitively establishes FRDA as a mitochondrial disease caused by loss of function of a nuclear-encoded protein. We also demonstrate that human frataxin contains a functional mitochondrial targeting signal, despite the low match with the mitochondrial targeting sequence consensus. A mitochondrial targeting signal was predicted from analysis of the yeast and mouse frataxin sequences (11 ). The mitochondrial targeting signal is located within the first 20 amino acids and is cleaved during mitochondrial import and maturation.
Mitochondrial dysfunction has long been suggested for Friedreich ataxia (20 ) because mitochondria have special relevance for the three most affected tissues in the disease, i.e. neurons, heart and pancreas. However, no consistent metabolic dysfunction had been observed to support a mitochondrial defect in Friedreich ataxia. Mitochondrial enzyme assays have so far been inconclusive, with unconfirmed reports of reduced activity for a few enzymes [for example glutamate dehydrogenase (21 ), mitochondrial malic enzyme (22 ), NADH cytochrome c reductase, succinate dehydrogenase and succinate cytochrome c reductase (23 )]. On the other hand, some mitochondrial diseases, such as MERRF (24 ), NARP (25 ) and Leigh syndrome (26 ), share clinical features with FRDA, including ataxia, peripheral neuropathy and cardiomyopathy. Striking clinical similarities between Friedreich ataxia and ataxia with isolated vitamin E deficiency (AVED) (27 ) may give a clue to frataxin function. AVED is caused by mutations in the [alpha]-tocopherol transfer protein (28 ). Vitamin E is a lipid-soluble antioxidant and free radical scavenger found in cell membranes. It is most abundant in the nuclear and mitochondrial membranes (29 ). In an in vitro assay on rat liver mitochondria, vitamin E, but not superoxide dismutase, was shown to have a protective role against both lipid peroxidation and mitochondrial DNA damage (30 ). On the other hand, mitochondria are known to be the most important physiological source of superoxide radicals in animal cells (31 ,32 ). Strong support in favour of free radical toxicity in Friedreich ataxia comes from studies of the yeast model. Knock-out of the corresponding frataxin gene led to hypersensitivity to hydrogen peroxide and iron (17 ,18 ). Iron measurements in the mutant yeast revealed a 10-fold increase in mitochondrial iron, while total iron content was roughly normal. Yeast frataxin was excluded from the mitochondrial outer membrane (17 ) and we found human frataxin in the mitochondrial membranes and crests, suggesting that frataxin is located at or near the inner mitochondrial membrane. Frataxin might therefore be involved with iron transport through the membrane or with electron transport by cytochromes and iron sulphur proteins of the mitochondrial inner membrane. Alteration of iron metabolism due to a reduction in frataxin would cause overproduction of free radicals within the mitochondria through the iron-catalysed Fenton chemistry, resulting in a neurodegenerative pathway similar to that seen in isolated vitamin E deficiency. Demonstration that mitochondrial iron metabolism is altered in Friedreich ataxia is needed to confirm that the most frequent hereditary ataxia can be added to the growing list of neurodegenerative diseases caused by free radicals and reactive oxygen species (33 ,34 ).
The complete coding sequence of frataxin was constructed by PCR amplification of a genomic fragment from positions +1 to +164 and cloning into the EcoRI and ClaI sites of the frataxin RACE cDNA (4 ), followed by addition of the XbaI-HindIII 3' fragment of EST clone 126314 (positions +270 to +1000) (Washington University-Merck EST Project). The PCR 5' primer contained an artificial EcoRI site introduced for cloning purposes. Synthesis of frataxin for immunization was achieved by cloning the entire coding sequence in the EcoRI and HindIII sites of the pATH1 prokaryotic expression vector (13 ) and production of a TrpE-frataxin fusion protein.
Frataxin was also expressed in eukaryotic cells by cloning the complete coding sequence or different fragments of the frataxin cDNA into the pTL1 expression vector (35 ). These fragments were generated by PCR with appropriate primers flanked by artificial restriction sites used for cloning. The same strategy was used to construct the GFP expression vectors (pEGFP-C1; Clontech) (36 ). Mutagenesis of the mitochondrial target sequence and of Gly130 to Val was carried out by PCR with specific primers containing the mutations. The ORF of all constructs (including the PATH1 constructs) was verified by sequencing. COS-1 and HeLa cells were transfected with the plasmids using calcium phosphate precipitation (37 ). The full-length frataxin clone in the pTL1 expression vector was used in an in vitro transcription and translation reaction with the TNT system (Promega).
Expression of the fusion protein by the pATH vector was induced by growing cells in M9 medium with indolacetic acid and without Trp (13 ). The fusion protein represented 50-80% of the proteins found in inclusion bodies. Inclusion bodies were solubilized in 8 M urea and proteins were renaturated by sequential dialysis with decreasing concentrations of urea. The synthetic peptide used for immunization (peptide A, CGLRTDIDATCTPRRASSNQRG) was conjugated to ovalbumin (Sigma) (38 ) prior to injection. Mouse injections and fusions were carried out as described (35 ). Hybridoma culture supernatants were screened using ELISA tests, immunocytochemistry on COS-1 cells expressing the full-length frataxin and Western blots. Five hybridomas were established and the corresponding antibodies were produced in mice ascites fluids. The weakly reacting antibodies were further purified from ascite fluids by affinity with the TrpE-frataxin fusion protein (39 ). Class and subclass were determined using an isotyping kit (Amersham). mAbs 1G2, 2D4, 2F10 and 1H1 are all IgG1,k and mAb 1D4 is a mixture IgG1,k and IgG2a,k.
Whole-cell extracts of transfected COS-1 and HeLa cells or of lymphoblastoid cell lines were obtained by homogenization in 50 mM Tris-HCl, pH 8.0, 10% (v/v) glycerol, 5 mM EDTA, 150 mM KCl, 1 mM phenylmethylsulphonyl fluoride followed by sonication. Insoluble material was removed by centrifugation at 10 000 g at 4oC for 10 min. Extracts of human tissues were obtained by grinding the frozen biopsies into powder with a pestle and mortar and homogenization in SDS lysis buffer containing 100 mM Tris-HCl, pH 9.0, 2% SDS, 5% [beta]-mercaptoethanol and 15% glycerol. The viscous extracts were heat denatured by boiling for 5 min followed by extensive sonication (2 min) to shear the DNA. Insoluble material was removed by centrifugation and protein concentration was estimated by SDS-PAGE with staining with Coomassie blue. Total protein extracts (50-200 [mu]g) were analysed on 12 or 15% SDS-polyacrylamide gels. Proteins were transferred to nitrocellulose membranes which were blocked with 4% non-fat milk and then incubated with the different primary antibodies, anti-frataxin (ascites fluid diluted 1:5000 or 1:10 000), anti-ataxin 3 (Y.Trottier, unpublished results), anti-actin (Sigma) or anti-subunit II of cytochrome c oxidase (a gift of Dr Anne Lombès) overnight at 4oC. Secondary antibody (goat anti-mouse or anti-rabbit IgG) coupled to peroxidase was used for detection of the reaction with Supersignal Substrate Western blotting (Pierce, IL) or with the ECL kit (Amersham), according to the manufacturers' instructions. Quantitation of frataxin in lymphoblast immunoblots was obtained by analysing autoradiograms on a video camera image with ISO 9000 software. The intensity of each frataxin band was corrected according to the intensity of the ~50 kDa tubulin band obtained in the same lane after rehybridization of the blot with control anti-tubulin antibodies (Amersham). One homozygous normal individual and two heterozygous carriers, assumed to have 50% frataxin, were used as controls for the amount of frataxin. Measurements were made in triplicate.
Differentiated striatal neurons and glia were generated from normal mouse E14 striatal CNS stem cell cultures isolated from embryonic CD1 albino mice, as described elsewhere (40 ). Briefly, following mechanical dissociation E14 single striatal cells were plated at a final density of 50 000 cells/cm2 in SATO/N2 basal medium in the presence of 20 ng/ml epidermal growth factor (EGF). Proliferating cultures were serially passaged every 6 days, three times, by mechanical dissociation and replating into the same EGF-containing medium. Six days after the last subculturing single clones (spheres) of cells were plated onto Matrigel (Becton Dickinson, Sparks, MD)-coated glass coverslips and grown in the presence of EGF for an additional 2 days after plating. Differentiation was then triggered by EGF removal and the cells were allowed to differentiate in EGF-free basal medium (control) for an additional 5 days. Viable cultures were exposed for 40 min at 37oC to 200 nM MitoTracker Green FM (containing a thiol-reactive chloromethyl moiety; Molecular Probes, Eugene, Oregon) diluted in control medium. Coverslips were rinsed once with control medium and once with phosphate-buffered saline (PBS), pH 7,4 prior to fixation for 15 min with 4% paraformaldehyde in PBS. After rinsing with PBS, coverslips were incubated for 10 min at room temperature in cold acetone followed by double washings with PBS, 10% NGS. Samples were then incubated for 1 h at 37oC with the primary anti-frataxin monoclonal antibody 1G2, diluted 1:100 in PBS, 10% NGS. After thorough washing with PBS, 10% NGS cells were reacted for 45 min at room temperature with secondary rhodamine (TRITC)-conjugated goat anti-mouse antibody (1:100; Boehringer Mannheim, Indianapolis, IN), rinsed three times in PBS and mounted on glass slides with Fluorsave (Calbiochem, La Jolla, CA). No labelling was ever observed in control experiments in which primary antibody and/or MitoTracker were omitted and neither was there evidence of cross-reactivity between MitoTracker and the secondary rhodamine (TRITC)-conjugated goat anti-mouse antibody.
Transfected HeLa cells, growing in Leighton tubes, were washed in PBS, fixed in 4% paraformaldehyde (20 min) and permeabilized in 0.05% Triton X-100 (3 * 5 min). Cells were then incubated for 16 h at 4oC with mAb 1G2 (ascites fluid 1:1000). Specifically bound antibodies were directly revealed by Cy3-conjugated goat anti-mouse antibody (Jackson Immunoresearch Laboratories). In co-localization experiments a second human autoimmune anti-mitochondrial primary antibody (Menarini diagnostics) was added and revealed with a FITC- or Texas red-conjugated anti-human antibody (Jackson Immunoresearch Laboratories).
For electron microscopy studies transfected cells growing in Leighton tubes were fixed for 5 h at 4oC with 4% paraformaldehyde, 0.1% glutaraldehyde, in 0.1 M phosphate buffer, pH 7.3, and then incubated for 16 h at 4oC with antibody 1G2 (1:1000) in the presence of 0.1% saponin. The primary antibody was revealed using the ABC method (Vector Laboratories Inc., CA) and diaminobenzidine as peroxidase substrate. Transfected cells were first detected at the optical level, then processed for standard EM methods, sliced in ultrathin 70 nm sections and transferred to electron microscopy grids. Control experiments, where the primary antibody was omitted, were performed in parallel.
The method of Lee et al. (41 ) was used to separate nuclei and cytoplasm. The cytoplasmic supernatant was further fractionated according to standard differential centrifugation methods. Protein concentration was determined by Bradford assay (42 ) and 100 [mu]g total protein were loaded per lane.
We wish to thank Dr A.Lombès for the anti-cytochrome c oxidase antibody, Dr R.Gatti for lymphoblastoid cell lines and Drs T.Gibson and F.Foury for sharing unpublished results. Thanks are due to Dr Cossée for analysis of patients and discussions and to H.Koutnikova for discussions. We are grateful to L.Reutenauer, S.Vicaire, F.Ruffenach, N.Jung, F.Cottin and V.Schultz for their technical assistance. This work was supported by funds from the Association Française contre les Myopathies (AFM), CNRS, INSERM and the Ministère de l'Enseignement Supérieur et de la Recherche (M.K.) and by grants from the National Institutes of Health (NS34192) and the Muscular Dystrophy Association, USA (M.P.). V.C. is the recipient of a fellowship from the EEC and L.M. is the recipient of a fellowship from the Medical Research Council of Canada. Y.T. is the recipient of a fellowship from the Hereditary Disease Foundation (USA).
1 Harding,A.E. (1983) Classification of the hereditary ataxias and paraplegias. Lancet, i, 1151-1155.
2 Oppenheimer,D.R. and Esiri,M.M. (1992) In Adams,J.H.,Corselli,J.A.N. and Duchen,L.W. (eds), Greenfield's Neuropathology. Edward Arnold, London, pp. 1015-1018.
3 Wallace,D.C., Shoffner,J.M., Trounce,I., Brown,M.D., Ballinger,S.W., Corral-Debrinski,M., Horton,T., Jun,A.S. and Lott,M.T. (1995) Mitochondrial DNA mutations in human degenerative diseases and aging. Biochim. Biophys. Acta, 1271, 141-151.MEDLINE Abstract
4 Campuzano,V., Montermini,L., Moltó,M.D., Pianese,L., Cossée,M., Cavalcanti,F., Monros,E., Rodius,F., Duclos,F., Monticelli,A., Zara,F., Cañizares,J., Koutnikova,H., Bidichandani,S., Gellera,C., Brice,A., Trouillas,P., De Michele,G., Filla,A., de Frutos,R., Palau,F., Patel,P.I., Di Donato,S., Mandel,J.-L., Cocozza,S., Koenig,M. and Pandolfo,M. (1996) Friedreich ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science, 271, 1423-1427.MEDLINE Abstract
5 Filla,A., De Michele,G., Cavalcanti,F., Pianese,L., Monticelli,A., Campanella,G. and Cocozza,S. (1996) The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. Am. J. Hum. Genet., 59, 554-560.MEDLINE Abstract
6 Dürr,A., Cossée,M., Agid,Y., Campuzano,V., Mignard,C., Penet,C., Mandel,J.-L., Brice,A. and Koenig,M. (1996) Clinical and genetic abnormalities in patients with Friedreich's ataxia. New Engl. J. Med., 335, 1169-1175.MEDLINE Abstract
7 Montermini,L., Richter,A., Morgan,K., Justice,C.M., Julien,D., Castelloti,B., Mercier,J., Poirier,J., Capazzoli,F., Bouchard,J.P., Lemieux,B., Mathieu,J., Vanasse,M., Seni,M.H., Graham,G., Andermann,F., Andermann,E., Melançon,S., Keats,B.J.B., Di Donato,S. and Pandolfo,M. (1997) Phenotypic variability in Friedreich ataxia: role of the associated GAA triplet repeat expansion. Annls Neurol., 41, 675-682.
8 Lamont,PJ., Davis,MB. and Wood,NW. (1997) Identification and sizing of the GAA trinucleotide repeat expansion of Friedreich's ataxia in 56 patients. Clinical and genetic correlates. Brain, 120, 673-680.MEDLINE Abstract
9 Monros,E., Moltó,M.D., Martinez,F., Cañizares,J., Blanca,J., Vilchez,J.J., Prieto,F., de Frutos,R. and Palau,F. (1997) Phenotype correlation and intergenerational dynamics of the Friedreich ataxia GAA trinucleotide repeat. Am. J. Hum. Genet., 61, 101-110.MEDLINE Abstract
11 Koutnikova,H., Campuzano,V., Foury,F., Dollé,P., Cazzalini,O. and Koenig,M. (1997) Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nature Genet., 16, 345-351.MEDLINE Abstract
12 Gibson,T.J., Koonin,E.V., Musco,G., Pastore,A. and Bork,P. (1996) Friedreich's ataxia protein: bacterial homologs point to mitochondrial dysfunction. Trends Neurosci., 19, 465-468.MEDLINE Abstract
13 Dieckmann,C.L. and Tzagoloff,A. (1985) Assembly of the mitochondrial membrane system. CBP6, a yeast nuclear gene necessary for synthesis of cytochrome b. J. Biol. Chem., 260, 1513-1520.MEDLINE Abstract
14 Barbeau,A., Roy,M., Sadibelouiz,M. and Wilensky,M.A. (1984) Recessive ataxia in Acadians and `Cajuns'. Can. J. Neurol. Sci., 11, 526-533.MEDLINE Abstract
15 Schatz,G. and Dobberstein,B. (1996) Common principles of protein translocation across membranes. Science, 271, 1519-1526.MEDLINE Abstract
16 Carvajal,J., Pook,M.A., dos Santos,M., Doudney,K., Hillermann,R., Minogue,S., Williamson,R., Hsuan,J.J. and Chamberlain,S. (1996) The Friedreich's ataxia gene encodes a novel phophatidylinositol-4-phosphate 5-kinase. Nature Genet., 14, 157-162.MEDLINE Abstract
17 Babcock,M., de Silva,D., Oaks,R., Davis-Kaplan,S., Jiralerspong,S., Montermini,L., Pandolfo,M. and Kaplan,J. (1997) Regulation of mitochondrial iron accumulation by Yfh1, a putative homolog of frataxin. Science, 276, 1709-1712.MEDLINE Abstract
18 Foury,F. and Cazzalini,O. (1997) Deletion of the yeast homologue of the human gene associated with Friedeich's ataxia elicits iron accumulation in mitochondria. FEBS Lett., in press.
19 Paul,R., Santucci,S., Saunieres,A., Desnuelle,C. and Paquis-Flucklinger,V. (1996) Rapid mapping of mitochondrial DNA deletions by large-fragment PCR. Trends Genet., 12, 131-132.MEDLINE Abstract
20 Cedarbaum,J.M. and Blass,J.P. (1986) Mitochondrial dysfunction and spinocerebellar degenerations. Neurochem. Pathol., 4, 43-63.MEDLINE Abstract
21 Barbeau,A., Charbonneau,M. and Cloutier,T. (1980) Leucocyte glutamate dehydrogenase in various hereditary ataxias. Can. J. Neurol. Sci., 7, 421-424.MEDLINE Abstract
22 Stumpf,D.A., Parks,J.K., Eguren,L.A. and Haas,R. (1982) Friedreich ataxia: III. Mitochondrial malic enzyme deficiency. Neurology, 32, 221-227.MEDLINE Abstract
23 Schöls,L., Reichmann,H., Amoiridis,G., Seibel,P., Wagener,S., Seufert,S. and Przuntek,H. (1996) Mitochondrial disorders in degenerative ataxias. Eur. J. Neurol., 3, 55-60.
24 Fukuhara,N., Tokiguchi,S., Shirakawa,K. and Tsubaki,T. (1980) Myoclonus epilepsy associated with ragged-red fibres (mitochondrial abnormalities): disease entity or a syndrome? Light- and electron-microscopic studies of two cases and review of literature. J. Neurol. Sci., 47, 117-133.MEDLINE Abstract
25 Holt,I.J., Harding,A.E., Petty,R.K.H. and Morgan-Hughes,A. (1990) A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am. J. Hum. Genet., 46, 428-433.MEDLINE Abstract
26 Pastores,G.M., Santorelli,F.M., Shanske,S., Gelb,B.D., Fyfe,B., Wolfe,D. and Willner,J.P. (1994) Leigh syndrome and hypertrophic cardiomyopathy in an infant with a mitochondrial DNA point mutation (T8993G). Am. J. Med. Genet., 50, 265-271.MEDLINE Abstract
27 Ben Hamida,M., Belal,S., Sirugo,G., Ben Hamida,C., Panayides,K., Ioannou,P., Beckmann,J., Mandel,J-L., Hentati,F., Koenig,M. and Middleton,L. (1993) Friedreich's ataxia phenotype not linked to chromosome 9 and associated with selective autosomal recessive vitamin E deficiency in two inbred Tunisian families. Neurology, 43, 2179-2183.MEDLINE Abstract
28 Ouahchi,K., Arita,M., Kayden,H.J., Hentati,F., Ben Hamida,M., Sokol,R., Arai,H., Inoue,K., Mandel,J.-L. and Koenig,M. (1995) Ataxia with isolated vitamin E deficiency is caused by mutations in the [alpha]-tocopherol transfer protein. Nature Genet., 9, 141-145.MEDLINE Abstract
29 Guarnieri,C., Flamigni,F. and Caldarera,C.R. (1980) Subcellular localization of alpha-tocopherol and its effect on RNA synthesis in perfused rabbit heart. Ital. J. Biochem., 29, 176-184.MEDLINE Abstract
30 Hruszkewycz,A.M. (1988) Evidence for mitochondrial DNA damage by lipid peroxidation. Biochem. Biophys. Res. Commun., 153, 191-197.MEDLINE Abstract
31 Naqui,A. and Chance,B. (1987) Steady-state kinetic approaches to complex biological systems. Cell Biophys., 11, 159-176.MEDLINE Abstract
32 Nohl,H. and Jordan,W. (1986) The mitochondrial site of superoxide formation. Biochem. Biophys. Res. Commun., 138, 533-539.MEDLINE Abstract
33 Gotz,M.E., Kunig,G., Riederer,P. and Youdim,M.B. (1994) Oxidative stress: free radical production in neural degeneration. Pharmacol. Ther., 63, 37-122.MEDLINE Abstract
35 Devys,D., Lutz,Y., Rouyer,N., Bellocq,J.P. and Mandel,J.L. (1993) The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation. Nature Genet., 4, 335-340.MEDLINE Abstract
36 Gerdes,H.H. and Kaether,C. (1996) Green fluorescent protein: applications in cell biology. FEBS Lett., 389, 44-47.MEDLINE Abstract
37 Gorman,C.M., Lane,D.P. and Rigby,P.W. (1984) High efficiency gene transfer into mammalian cells. Phil. Trans. R. Soc. Lond. (Biol.), 307, 343-346.MEDLINE Abstract
38 Harlow,E. and Lane,D. (1988) Antibodies: A Laboratory Manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.
39 Hoffman,E.P., Brown,R.H.,Jr and Kunkel,L.M. (1987) Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell, 51, 919-928.MEDLINE Abstract
40 Vescovi,A.L., Reynolds,B.A., Fraser,D.D. and Weiss,S. (1993) bFGF regulates the proliferative fate of unipotent (neuronal) and bipotent (neuronal/astroglial) EGF-generated CNS progenitor cells. Neuron, 11, 951-966.MEDLINE Abstract
41 Lee,K.A., Bindereif,A. and Green,M.R. (1988) A small-scale procedure for preparation of nuclear extracts that support efficient transcription and pre-mRNA splicing. Gene Anal. Techniques, 5, 22-31.
42 Bradford,M.M. (1976) A rapid sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem, 72, 248-254.MEDLINE Abstract
*To whom correspondence should be addressed. Tel: +33 3 8865 3399; Fax: +33 3 8865 3246; Email: mkoenig@igbmc.u-strasbg.fr
F. Fortuna, P. Barboni, R. Liguori, M. L. Valentino, G. Savini, C. Gellera, C. Mariotti, G. Rizzo, C. Tonon, D. Manners, et al. Visual system involvement in patients with Friedreich's ataxia
Brain,
January 1, 2009;
132(1):
116 - 123.
[Abstract][Full Text][PDF]
E. Soragni, D. Herman, S. Y. R. Dent, J. M. Gottesfeld, R. D. Wells, and M. Napierala Long intronic GAA*TTC repeats induce epigenetic changes and reporter gene silencing in a molecular model of Friedreich ataxia
Nucleic Acids Res.,
November 1, 2008;
36(19):
6056 - 6065.
[Abstract][Full Text][PDF]
F. Auchere, R. Santos, S. Planamente, E. Lesuisse, and J.-M. Camadro Glutathione-dependent redox status of frataxin-deficient cells in a yeast model of Friedreich's ataxia
Hum. Mol. Genet.,
September 15, 2008;
17(18):
2790 - 2802.
[Abstract][Full Text][PDF]
S. Long, M. Jirku, F. J. Ayala, and J. Lukes Mitochondrial localization of human frataxin is necessary but processing is not for rescuing frataxin deficiency in Trypanosoma brucei
PNAS,
September 9, 2008;
105(36):
13468 - 13473.
[Abstract][Full Text][PDF]
S. Al-Mahdawi, R. M. Pinto, O. Ismail, D. Varshney, S. Lymperi, C. Sandi, D. Trabzuni, and M. Pook The Friedreich ataxia GAA repeat expansion mutation induces comparable epigenetic changes in human and transgenic mouse brain and heart tissues
Hum. Mol. Genet.,
March 1, 2008;
17(5):
735 - 746.
[Abstract][Full Text][PDF]
L. M. Pollard, R. L. Bourn, and S. I. Bidichandani Repair of DNA double-strand breaks within the (GAA*TTC)n sequence results in frequent deletion of the triplet-repeat sequence
Nucleic Acids Res.,
February 2, 2008;
36(2):
489 - 500.
[Abstract][Full Text][PDF]
P. R. Anderson, K. Kirby, W. C. Orr, A. J. Hilliker, and J. P. Phillips Hydrogen peroxide scavenging rescues frataxin deficiency in a Drosophila model of Friedreich's ataxia
PNAS,
January 15, 2008;
105(2):
611 - 616.
[Abstract][Full Text][PDF]
J. R Maring and E. Croarkin Presentation and Progression of Friedreich Ataxia and Implications for Physical Therapist Examination
Physical Therapy,
December 1, 2007;
87(12):
1687 - 1696.
[Abstract][Full Text][PDF]
L. M. Pollard, Y. K. Chutake, P. M. Rindler, and S. I. Bidichandani Deficiency of RecA-dependent RecFOR and RecBCD pathways causes increased instability of the (GAA{middle dot}TTC)n sequence when GAA is the lagging strand template
Nucleic Acids Res.,
November 29, 2007;
35(20):
6884 - 6894.
[Abstract][Full Text][PDF]
A. Martelli, M. Wattenhofer-Donze, S. Schmucker, S. Bouvet, L. Reutenauer, and H. Puccio Frataxin is essential for extramitochondrial Fe S cluster proteins in mammalian tissues
Hum. Mol. Genet.,
November 15, 2007;
16(22):
2651 - 2658.
[Abstract][Full Text][PDF]
M. M. Krasilnikova, M. L. Kireeva, V. Petrovic, N. Knijnikova, M. Kashlev, and S. M. Mirkin Effects of Friedreich's ataxia (GAA)n{middle dot}(TTC)n repeats on RNA synthesis and stability
Nucleic Acids Res.,
February 28, 2007;
35(4):
1075 - 1084.
[Abstract][Full Text][PDF]
J. V. Llorens, J. A. Navarro, M. J. Martinez-Sebastian, M. K. Baylies, S. Schneuwly, J. A. Botella, and M. D. Molto Causative role of oxidative stress in a Drosophila model of Friedreich ataxia
FASEB J,
February 1, 2007;
21(2):
333 - 344.
[Abstract][Full Text][PDF]
Y. Zhang, E. R. Lyver, S. A. B. Knight, D. Pain, E. Lesuisse, and A. Dancis Mrs3p, Mrs4p, and Frataxin Provide Iron for Fe-S Cluster Synthesis in Mitochondria
J. Biol. Chem.,
August 11, 2006;
281(32):
22493 - 22502.
[Abstract][Full Text][PDF]
E. Vivas, E. Skovran, and D. M. Downs Salmonella enterica Strains Lacking the Frataxin Homolog CyaY Show Defects in Fe-S Cluster Metabolism In Vivo
J. Bacteriol.,
February 1, 2006;
188(3):
1175 - 1179.
[Abstract][Full Text][PDF]
T. J. Schulz, R. Thierbach, A. Voigt, G. Drewes, B. Mietzner, P. Steinberg, A. F. H. Pfeiffer, and M. Ristow Induction of Oxidative Metabolism by Mitochondrial Frataxin Inhibits Cancer Growth: OTTO WARBURG REVISITED
J. Biol. Chem.,
January 13, 2006;
281(2):
977 - 981.
[Abstract][Full Text][PDF]
R. Thierbach, T. J. Schulz, F. Isken, A. Voigt, B. Mietzner, G. Drewes, J.-C. von Kleist-Retzow, R. J. Wiesner, M. A. Magnuson, H. Puccio, et al. Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice
Hum. Mol. Genet.,
December 15, 2005;
14(24):
3857 - 3864.
[Abstract][Full Text][PDF]
J R Porter and T G Barrett Monogenic syndromes of abnormal glucose homeostasis: clinical review and relevance to the understanding of the pathology of insulin resistance and {beta} cell failure
J. Med. Genet.,
December 1, 2005;
42(12):
893 - 902.
[Abstract][Full Text][PDF]
P. R. Anderson, K. Kirby, A. J. Hilliker, and J. P. Phillips RNAi-mediated suppression of the mitochondrial iron chaperone, frataxin, in Drosophila
Hum. Mol. Genet.,
November 15, 2005;
14(22):
3397 - 3405.
[Abstract][Full Text][PDF]
F. Acquaviva, I. De Biase, L. Nezi, G. Ruggiero, F. Tatangelo, C. Pisano, A. Monticelli, C. Garbi, A. M. Acquaviva, and S. Cocozza Extra-mitochondrial localisation of frataxin and its association with IscU1 during enterocyte-like differentiation of the human colon adenocarcinoma cell line Caco-2
J. Cell Sci.,
September 1, 2005;
118(17):
3917 - 3924.
[Abstract][Full Text][PDF]
P. Gonzalez-Cabo, R. P. Vazquez-Manrique, M. A. Garcia-Gimeno, P. Sanz, and F. Palau Frataxin interacts functionally with mitochondrial electron transport chain proteins
Hum. Mol. Genet.,
August 1, 2005;
14(15):
2091 - 2098.
[Abstract][Full Text][PDF]
P. E. Hart, R. Lodi, B. Rajagopalan, J. L. Bradley, J. G. Crilley, C. Turner, A. M. Blamire, D. Manners, P. Styles, A. H. V. Schapira, et al. Antioxidant Treatment of Patients With Friedreich Ataxia: Four-Year Follow-up
Arch Neurol,
April 1, 2005;
62(4):
621 - 626.
[Abstract][Full Text][PDF]
I. Napier, P. Ponka, and D. R. Richardson Iron trafficking in the mitochondrion: novel pathways revealed by disease
Blood,
March 1, 2005;
105(5):
1867 - 1874.
[Abstract][Full Text][PDF]
B. Sturm, U. Bistrich, M. Schranzhofer, J. P. Sarsero, U. Rauen, B. Scheiber-Mojdehkar, H. de Groot, P. Ioannou, and F. Petrat Friedreich's Ataxia, No Changes in Mitochondrial Labile Iron in Human Lymphoblasts and Fibroblasts: A DECREASE IN ANTIOXIDATIVE CAPACITY?
J. Biol. Chem.,
February 25, 2005;
280(8):
6701 - 6708.
[Abstract][Full Text][PDF]
H. Seznec, D. Simon, C. Bouton, L. Reutenauer, A. Hertzog, P. Golik, V. Procaccio, M. Patel, J.-C. Drapier, M. Koenig, et al. Friedreich ataxia: the oxidative stress paradox
Hum. Mol. Genet.,
February 15, 2005;
14(4):
463 - 474.
[Abstract][Full Text][PDF]
O. Stehling, H.-P. Elsasser, B. Bruckel, U. Muhlenhoff, and R. Lill Iron-sulfur protein maturation in human cells: evidence for a function of frataxin
Hum. Mol. Genet.,
December 1, 2004;
13(23):
3007 - 3015.
[Abstract][Full Text][PDF]
L. M. Pollard, R. Sharma, M. Gomez, S. Shah, M. B. Delatycki, L. Pianese, A. Monticelli, B. J.B. Keats, and S. I. Bidichandani Replication-mediated instability of the GAA triplet repeat mutation in Friedreich ataxia
Nucleic Acids Res.,
November 8, 2004;
32(19):
5962 - 5971.
[Abstract][Full Text][PDF]
P. Ciotti, E. Di Maria, E. Bellone, F. Ajmar, and P. Mandich Triplet Repeat Primed PCR (TP PCR) in Molecular Diagnostic Testing for Friedreich Ataxia
J. Mol. Diagn.,
November 1, 2004;
6(4):
285 - 289.
[Abstract][Full Text][PDF]
C. M. Everett and N. W. Wood Trinucleotide repeats and neurodegenerative disease
Brain,
November 1, 2004;
127(11):
2385 - 2405.
[Abstract][Full Text][PDF]
L Pianese, M Turano, M S Lo Casale, I De Biase, M Giacchetti, A Monticelli, C Criscuolo, A Filla, and S Cocozza Real time PCR quantification of frataxin mRNA in the peripheral blood leucocytes of Friedreich ataxia patients and carriers
J. Neurol. Neurosurg. Psychiatry,
July 1, 2004;
75(7):
1061 - 1063.
[Abstract][Full Text][PDF]
M. M. Krasilnikova and S. M. Mirkin Replication Stalling at Friedreich's Ataxia (GAA)n Repeats In Vivo
Mol. Cell. Biol.,
March 15, 2004;
24(6):
2286 - 2295.
[Abstract][Full Text][PDF]
V. N. Potaman, E. A. Oussatcheva, Y. L. Lyubchenko, L. S. Shlyakhtenko, S. I. Bidichandani, T. Ashizawa, and R. R. Sinden Length-dependent structure formation in Friedreich ataxia (GAA)n{middle dot}(TTC)n repeats at neutral pH
Nucleic Acids Res.,
February 20, 2004;
32(3):
1224 - 1231.
[Abstract][Full Text][PDF]
M. Napierala, R. Dere, A. Vetcher, and R. D. Wells Structure-dependent Recombination Hot Spot Activity of GAA{middle dot}TTC Sequences from Intron 1 of the Friedreich's Ataxia Gene
J. Biol. Chem.,
February 20, 2004;
279(8):
6444 - 6454.
[Abstract][Full Text][PDF]
G. Karthikeyan, J. H. Santos, M. A. Graziewicz, W. C. Copeland, G. Isaya, B. V. Houten, and M. A. Resnick Reduction in frataxin causes progressive accumulation of mitochondrial damage
Hum. Mol. Genet.,
December 15, 2003;
12(24):
3331 - 3342.
[Abstract][Full Text][PDF]
M. L. Jauslin, T. Wirth, T. Meier, and F. Schoumacher A cellular model for Friedreich Ataxia reveals small-molecule glutathione peroxidase mimetics as novel treatment strategy
Hum. Mol. Genet.,
November 15, 2002;
11(24):
3055 - 3063.
[Abstract][Full Text][PDF]
L. Pianese, L. Busino, I. De Biase, T. de Cristofaro, M. S. Lo Casale, P. Giuliano, A. Monticelli, M. Turano, C. Criscuolo, A. Filla, et al. Up-regulation of c-Jun N-terminal kinase pathway in Friedreich's ataxia cells
Hum. Mol. Genet.,
November 1, 2002;
11(23):
2989 - 2996.
[Abstract][Full Text][PDF]
A. A. Vetcher, M. Napierala, R. R. Iyer, P. D. Chastain, J. D. Griffith, and R. D. Wells Sticky DNA, a Long GAA{middle dot}GAA{middle dot}TTC Triplex That Is Formed Intramolecularly, in the Sequence of Intron 1 of the Frataxin Gene
J. Biol. Chem.,
October 11, 2002;
277(42):
39217 - 39227.
[Abstract][Full Text][PDF]
S. Adinolfi, M. Trifuoggi, A. S. Politou, S. Martin, and A. Pastore A structural approach to understanding the iron-binding properties of phylogenetically different frataxins
Hum. Mol. Genet.,
August 1, 2002;
11(16):
1865 - 1877.
[Abstract][Full Text][PDF]
E. M. Becker, J. M. Greer, P. Ponka, and D. R. Richardson Erythroid differentiation and protoporphyrin IX down-regulate frataxin expression in Friend cells: characterization of frataxin expression compared to molecules involved in iron metabolism and hemoglobinization
Blood,
May 15, 2002;
99(10):
3813 - 3822.
[Abstract][Full Text][PDF]
M. G. Yefimova, J.-C. Jeanny, N. Keller, C. Sergeant, X. Guillonneau, C. Beaumont, and Y. Courtois Impaired Retinal Iron Homeostasis Associated with Defective Phagocytosis in Royal College of Surgeons Rats
Invest. Ophthalmol. Vis. Sci.,
February 1, 2002;
43(2):
537 - 545.
[Abstract][Full Text][PDF]
A H V Schapira The "new" mitochondrial disorders
J. Neurol. Neurosurg. Psychiatry,
February 1, 2002;
72(2):
144 - 149.
[Abstract][Full Text][PDF]
C. N. Roy and N. C. Andrews Recent advances in disorders of iron metabolism: mutations, mechanisms and modifiers
Hum. Mol. Genet.,
October 1, 2001;
10(20):
2181 - 2186.
[Abstract][Full Text][PDF]
M. A. Huynen, B. Snel, P. Bork, and T. J. Gibson The phylogenetic distribution of frataxin indicates a role in iron-sulfur cluster protein assembly
Hum. Mol. Genet.,
October 1, 2001;
10(21):
2463 - 2468.
[Abstract][Full Text][PDF]
R. Lodi, B. Rajagopalan, A. M Blamire, J.M. Cooper, C. H Davies, J. L Bradley, P. Styles, and A. H.V Schapira Cardiac energetics are abnormal in Friedreich ataxia patients in the absence of cardiac dysfunction and hypertrophy: An in vivo 31P magnetic resonance spectroscopy study
Cardiovasc Res,
October 1, 2001;
52(1):
111 - 119.
[Abstract][Full Text][PDF]
A. Mazarib, L. Xiong, M.Y. Neufeld, M. Birnbaum, A.D. Korczyn, M. Pandolfo, and S.F. Berkovic Unverricht-Lundborg disease in a five-generation Arab family: Instability of dodecamer repeats
Neurology,
September 25, 2001;
57(6):
1050 - 1054.
[Abstract][Full Text][PDF]
M. M. Santos, K. Ohshima, and M. Pandolfo Frataxin deficiency enhances apoptosis in cells differentiating into neuroectoderm
Hum. Mol. Genet.,
September 1, 2001;
10(18):
1935 - 1944.
[Abstract][Full Text][PDF]
G. Tan, L.-S. Chen, B. Lonnerdal, C. Gellera, F. A. Taroni, and G. A. Cortopassi Frataxin expression rescues mitochondrial dysfunctions in FRDA cells
Hum. Mol. Genet.,
September 1, 2001;
10(19):
2099 - 2107.
[Abstract][Full Text][PDF]
E. Grabczyk and K. Usdin Alleviating transcript insufficiency caused by Friedreich's ataxia triplet repeats
Nucleic Acids Res.,
December 15, 2000;
28(24):
4930 - 4937.
[Abstract][Full Text][PDF]
T. Sherer and J. T. Greenamyre A therapeutic target and biomarker in Friedreich's ataxia
Neurology,
December 12, 2000;
55(11):
1600 - 1601.
[Full Text][PDF]
M. J. Sobrido and D. H. Geschwind Molecular Genetics and Inherited Ataxias: Redefining Phenotypes and Pathogenesis
Neuroscientist,
December 1, 2000;
6(6):
465 - 474.
[Abstract][PDF]
G CASTELNOVO, B BIOLSI, A BARBAUD, P LABAUGE, and M SCHMITT Isolated spastic paraparesis leading to diagnosis of Friedreich's ataxia
J. Neurol. Neurosurg. Psychiatry,
November 1, 2000;
69(5):
693 - 693.
[Full Text]
M. A POOK, S. A H AL-MAHDAWI, N. H THOMAS, R. APPLETON, A. NORMAN, R. MOUNTFORD, and S. CHAMBERLAIN Identification of three novel frameshift mutations in patients with Friedreich's ataxia
J. Med. Genet.,
November 1, 2000;
37(11):
38e - 38.
[Full Text]
M. Ristow, M. F. Pfister, A. J. Yee, M. Schubert, L. Michael, C.-Y. Zhang, K. Ueki, M. D. Michael II, B. B. Lowell, and C. R. Kahn Frataxin activates mitochondrial energy conversion and oxidative phosphorylation
PNAS,
October 12, 2000;
(2000)
220403797.
[Abstract][Full Text]
P. Cavadini, C. Gellera, P. I. Patel, and G. Isaya Human frataxin maintains mitochondrial iron homeostasis in Saccharomyces cerevisiae
Hum. Mol. Genet.,
October 1, 2000;
9(17):
2523 - 2530.
[Abstract][Full Text][PDF]
S.-J. Cho, M. G. Lee, J. K. Yang, J. Y. Lee, H. K. Song, and S. W. Suh Crystal structure of Escherichia coli CyaY protein reveals a previously unidentified fold for the evolutionarily conserved frataxin family
PNAS,
July 19, 2000;
(2000)
160270897.
[Abstract][Full Text]
E. Grabczyk and K. Usdin The GAATTC triplet repeat expanded in Friedreich's ataxia impedes transcription elongation by T7 RNA polymerase in a length and supercoil dependent manner
Nucleic Acids Res.,
July 15, 2000;
28(14):
2815 - 2822.
[Abstract][Full Text][PDF]
M. Cossee, H. Puccio, A. Gansmuller, H. Koutnikova, A. Dierich, M. LeMeur, K. Fischbeck, P. Dolle, and M. Koenig Inactivation of the Friedreich ataxia mouse gene leads to early embryonic lethality without iron accumulation
Hum. Mol. Genet.,
May 1, 2000;
9(8):
1219 - 1226.
[Abstract][Full Text][PDF]
M. L McCormack, R. P Guttmann, M. Schumann, J. M Farmer, C. A Stolle, V. Campuzano, M. Koenig, and D. R Lynch Frataxin point mutations in two patients with Friedreich's ataxia and unusual clinical features
J. Neurol. Neurosurg. Psychiatry,
May 1, 2000;
68(5):
661 - 664.
[Abstract][Full Text]
H. Puccio Recent advances in the molecular pathogenesis of Friedreich ataxia
Hum. Mol. Genet.,
April 1, 2000;
9(6):
887 - 892.
[Abstract][Full Text][PDF]
C. J. Cummings and H. Y. Zoghbi Fourteen and counting: unraveling trinucleotide repeat diseases
Hum. Mol. Genet.,
April 1, 2000;
9(6):
909 - 916.
[Abstract][Full Text][PDF]
O. S. Chen and J. Kaplan CCC1 Suppresses Mitochondrial Damage in the Yeast Model of Friedreich's Ataxia by Limiting Mitochondrial Iron Accumulation
J. Biol. Chem.,
March 10, 2000;
275(11):
7626 - 7632.
[Abstract][Full Text][PDF]
S. I. Bidichandani, C. A. Garcia, P. I. Patel, and M. M. Dimachkie Very Late-Onset Friedreich Ataxia Despite Large GAA Triplet Repeat Expansions
Arch Neurol,
February 1, 2000;
57(2):
246 - 251.
[Abstract][Full Text][PDF]
G. De Michele, A. Filla, F. Cavalcanti, A. Tammaro, A. Monticelli, L. Pianese, F. Di Salle, A. Perretti, L. Santoro, G. Caruso, et al. Atypical Friedreich ataxia phenotype associated with a novel missense mutation in the X25 gene
Neurology,
January 25, 2000;
54(2):
496 - 496.
[Abstract][Full Text][PDF]
J.L. Bradley, J.C. Blake, S. Chamberlain, P.K. Thomas, J.M. Cooper, and A.H.V. Schapira Clinical, biochemical and molecular genetic correlations in Friedreich's ataxia
Hum. Mol. Genet.,
January 22, 2000;
9(2):
275 - 282.
[Abstract][Full Text][PDF]
M. B Delatycki, R. Williamson, and S. M Forrest Friedreich ataxia: an overview
J. Med. Genet.,
January 1, 2000;
37(1):
1 - 8.
[Abstract][Full Text]
M. Pandolfo Molecular Pathogenesis of Friedreich Ataxia
Arch Neurol,
October 1, 1999;
56(10):
1201 - 1208.
[Abstract][Full Text][PDF]
J. Kaplan Friedreich's ataxia is a mitochondrial disorder
PNAS,
September 28, 1999;
96(20):
10948 - 10949.
[Full Text][PDF]
R. Lodi, J. M. Cooper, J. L. Bradley, D. Manners, P. Styles, D. J. Taylor, and A. H. V. Schapira Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia
PNAS,
September 28, 1999;
96(20):
11492 - 11495.
[Abstract][Full Text][PDF]
S. S. Branda, P. Cavadini, J. Adamec, F. Kalousek, F. Taroni, and G. Isaya Yeast and Human Frataxin Are Processed to Mature Form in Two Sequential Steps by the Mitochondrial Processing Peptidase
J. Biol. Chem.,
August 6, 1999;
274(32):
22763 - 22769.
[Abstract][Full Text][PDF]
J. B. Martin Molecular Basis of the Neurodegenerative Disorders
N. Engl. J. Med.,
June 24, 1999;
340(25):
1970 - 1980.
[Full Text][PDF]
D. C. Radisky, M. C. Babcock, and J. Kaplan The Yeast Frataxin Homologue Mediates Mitochondrial Iron Efflux. EVIDENCE FOR A MITOCHONDRIAL IRON CYCLE
J. Biol. Chem.,
February 19, 1999;
274(8):
4497 - 4499.
[Abstract][Full Text][PDF]
K. Ohshima, L. Montermini, R. D. Wells, and M. Pandolfo Inhibitory Effects of Expanded GAA·TTC Triplet Repeats from Intron I of the Friedreich Ataxia Gene on Transcription and Replication in Vivo
J. Biol. Chem.,
June 5, 1998;
273(23):
14588 - 14595.
[Abstract][Full Text][PDF]
S. Dhe-Paganon, R. Shigeta, Y.-I. Chi, M. Ristow, and S. E. Shoelson Crystal Structure of Human Frataxin
J. Biol. Chem.,
September 29, 2000;
275(40):
30753 - 30756.
[Abstract][Full Text][PDF]
P. Cavadini, J. Adamec, F. Taroni, O. Gakh, and G. Isaya Two-step Processing of Human Frataxin by Mitochondrial Processing Peptidase. PRECURSOR AND INTERMEDIATE FORMS ARE CLEAVED AT DIFFERENT RATES
J. Biol. Chem.,
December 22, 2000;
275(52):
41469 - 41475.
[Abstract][Full Text][PDF]
N. Sakamoto, J. E. Larson, R. R. Iyer, L. Montermini, M. Pandolfo, and R. D. Wells GGA{middle dot}TCC-interrupted Triplets in Long GAA{middle dot}TTC Repeats Inhibit the Formation of Triplex and Sticky DNA Structures, Alleviate Transcription Inhibition, and Reduce Genetic Instabilities
J. Biol. Chem.,
July 13, 2001;
276(29):
27178 - 27187.
[Abstract][Full Text][PDF]
N. Sakamoto, K. Ohshima, L. Montermini, M. Pandolfo, and R. D. Wells Sticky DNA, a Self-associated Complex Formed at Long GAA{middle dot}TTC Repeats in Intron 1 of the Frataxin Gene, Inhibits Transcription
J. Biol. Chem.,
July 13, 2001;
276(29):
27171 - 27177.
[Abstract][Full Text][PDF]
S.-J. Cho, M. G. Lee, J. K. Yang, J. Y. Lee, H. K. Song, and S. W. Suh Crystal structure of Escherichia coli CyaY protein reveals a previously unidentified fold for the evolutionarily conserved frataxin family
PNAS,
August 1, 2000;
97(16):
8932 - 8937.
[Abstract][Full Text][PDF]
M. Ristow, M. F. Pfister, A. J. Yee, M. Schubert, L. Michael, C.-Y. Zhang, K. Ueki, M. D. Michael II, B. B. Lowell, and C. R. Kahn Frataxin activates mitochondrial energy conversion and oxidative phosphorylation
PNAS,
October 24, 2000;
97(22):
12239 - 12243.
[Abstract][Full Text][PDF]
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